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ADRB2 (adrenoceptor beta 2, surface)

Written2014-02Denise Tostes Oliveira, Diego Mauricio Bravo-Calderón
Department of Stomatology, Area of Pathology, Bauru School of Dentistry - University of Sao Paulo, Bauru, Brazil

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HGNC Alias symbADRBR
HGNC Previous nameADRB2R
HGNC Previous nameadrenergic, beta-2-, receptor, surface
 adrenoceptor beta 2, surface
LocusID (NCBI) 154
Atlas_Id 43818
Location 5q32  [Link to chromosome band 5q32]
Location_base_pair Starts at 148826611 and ends at 148828623 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping ADRB2.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)


Description ADBR2 gene spans about 2,04 kb and consists of one exon.
Transcription ADBR2 no has introns in either their coding or untranslated sequences. The primary transcripts are processed at their 5' and 3' ends like other premessenger RNAs, but no splicing is needed.
Pseudogene No pseudogenes have been reported.


Description β2 adrenergic receptor is a member of the superfamily of G-protein coupled receptors (GPCRs) (McGraw and Liggett, 2005; Johnson, 2006). The receptor is comprised of 413 amino acid residues of approximately 46500 daltons (Johnson, 2006). β2 adrenergic receptor is N-glycosylated at amino acids 6, 15, and 187; these are important for roper insertion of the receptor into the membrane as well as for agonist trafficking (McGraw and Liggett, 2005; Johnson, 2006).
Expression β2 adrenergic receptor is widely distributed, this protein is expressed by airway smooth muscle (30-40000 per cell), epithelial and endothelial cells of the lung, smooth muscle of blood vessels, skeletal muscle, mast cells, lymphocytes, oral and skin keratinocytes and also by diverse cancer cells (Kohm and Sanders, 2001; Lutgendorf et al., 2003; Johnson, 2006; Sood et al., 2006; Thaker et al., 2006; Yang et al., 2006; Sastry et al., 2007; Yu et al., 2007; Liu et al., 2008a; Liu et al., 2008b; Shang et al., 2009; Sivamani et al., 2009; Yang et al., 2009; Bernabé et al., 2011; Bravo-Calderón et al., 2011-2012; Steenhuis et al., 2011; Zhang et al., 2011; Loenneke et al., 2012).
Localisation β2 adrenergic receptor is a transmembrane protein. Like all GPCRs, the β2 adrenergic receptor has seven transmembrane a domains that form a pocket containing binding sites for agonists and competitive antagonists (McGraw and Liggett, 2005; Johnson, 2006). There are 3 extracellular loops, with one being the amino terminus, and 3 intracellular loops, with a carboxy terminus (McGraw and Liggett, 2005; Johnson, 2006).
Function Agonist binding of β2 adrenergic receptor results in activation of Gs protein. The Gs protein a subunit stimulates adenylyl cyclase to generate cyclic 3'-5'-adenosine monophosphate (cAMP), which in sequence activates the cAMP-dependent protein kinase A (PKA) and the agonist-occupied receptor is phosphorylated. After phosphorylation, the receptor switches its coupling specificity to Gi. GTP-bound Giα dissociates from the heterodimeric Gβγ, and free Gβγ subunits mediate activation of the MAP kinase signaling pathway in the same way as Gi-coupled receptors. Increase of intracellular cAMP levels leads diverse cell functions as cell proliferation, differentiation, angiogenesis and migration (Daaka et al., 1997).
  Activation of protein kinase A (PKA) by signal transduction of β2 adrenergic receptor (adapted of Rosenbaum et al., 2009).

Implicated in

Entity Ovarian carcinoma
Note Reverse transcriptase-PCR studies indicated constitutive expression of β2 adrenergic receptor on ovarian carcinoma cell lines (Lutgendorf et al., 2003). Lutgendorf et al. (Lutgendorf et al., 2003) investigated the effects of norepinephrine and isoproterenol (a nonspecific-adrenergic agonist) on the production of vascular endothelial growth factor (VEGF) by ovarian cancer cell lines; and found that both, norepinephrine and isoproterenol, significantly enhanced VEGF production. These effects were blocked by thenon-specific β antagonist propranolol, supporting a role foradrenergic receptors in these experimental effects.
Norepinephrine was later found to increase the in vitro invasive potential of ovarian cancer cells, an effect that was blocked by propranolol (Sood et al., 2006). Norepinephrine also increased tumor cell expression of matrix metalloproteinase-2 (MMP-2) and MMP-9, and pharmacologic blockade of MMPs abrogated the effects of norepinephrine on tumor cell invasive potential (Sood et al., 2006).
In the same way, Thaker et al. (Thaker et al., 2006) correlated chronic behavioral stress with higher levels of tissue catecholamines and more invasive growth of ovarian carcinoma cells in an orthotopic mouse model. These effects were mediated through β2 adrenergic receptor activation of PKA signaling pathway (Thaker et al., 2006). Tumors in stressed animals showed increased vascularization and enhanced expression of VEGF, MMP2 and MMP9; these effects could be abrogated by propranolol (Thaker et al., 2006).
Entity Prostate cancer
Note β2 adrenergic receptor signaling was related to prostate cancer cell progression (Sastry et al., 2007; Zhang et al., 2011). β2 adrenergic receptor activation of PKA signaling pathway has been associated with reduction of sensitivity of prostate cancer cells to apoptosis (Sastry et al., 2007) and promotion of cell proliferation and cell migration (Zhang at al., 2011).
Contrastingly, other investigation demonstrated that the genetic silencing of β2 adrenergic receptor increases cell migration and invasion of normal prostate cells and that the weak expression of this protein is associated with metastases and with worst survival rates in prostate cancer patients (Yu et al., 2007).
Entity Esophageal squamous cell carcinoma
Note Liu et al. (Liu et al., 2008b) demonstrated that stimulation of β2 adrenergic receptor with epinephrine significantly increase the esophageal cancer cell proliferation accompanied by elevation of the expression of VEGF, VEGF receptor VEGFR-1 and VEGFR-2. In addition, it has been shown that the epidermal growth factor mediates the mitogenic signals in esophageal cancer cells through transactivation of β2 adrenergic receptor (Liu et al., 2008a).
Entity Oral squamous cell carcinoma (OSCC)
Note Genetic and protein expression of β2 adrenergic receptor was demonstrated in OSCC by using RT-PCR assay, Western blot and immunohistochemistry (Shang et al., 2009; Bernabé et al., 2011; Bravo-Calderón et al., 2011-2012). Investigations performed in different oral cancer cell lines demonstrated that β2 adrenergic receptor signaling by norepinephrine increases cell proliferation and invasion, and upregulates interleukin-6 (IL-6) gene expression and protein release (Shang et al., 2009; Bernabé et al., 2011). Furthermore, Shang et al. (Shang et al., 2009) reported that malignant cell positive immunoexpression of β2-AR was significantly correlated with age, tumor size, clinical stage and cervical lymph node metastasis in OSCC patients, and that β2-AR may play an important role in the formation and metastasis of oral cancer. However, a retrospective clinical study of a large number of patients showed that patients with OSCC who exhibited strong β2-AR immunohistochemical expression by malignant epithelial cells demonstrated higher survival rates compared to patients with weak/negative β2-AR expression (Bravo-Calderón et al., 2011-2012). Therefore, further clinical and laboratory studies are warranted to elucidate the role of β2 adrenergic receptor activation in oral squamous cell carcinoma.
Entity Various cancers
Note β2 adrenergic receptor was also immunohistochemically identified in nasopharyngeal carcinoma (Yang et al., 2006) and in melanoma (Yang et al., 2009). Norepinephrine treatment increased MMP-2, MMP-9, and VEGF levels in culture supernatants of nasopharyngeal carcinoma cells lines (Yang et al., 2006); as well upregulated the production of VEGF, interleukin (IL)-8, and IL-6 in human melanoma tumor cell lines (Yang et al., 2009).


Stress hormones increase cell proliferation and regulates interleukin-6 secretion in human oral squamous cell carcinoma cells.
Bernabe DG, Tamae AC, Biasoli ER, Oliveira SH.
Brain Behav Immun. 2011 Mar;25(3):574-83. doi: 10.1016/j.bbi.2010.12.012. Epub 2010 Dec 25.
PMID 21187140
Prognostic significance of beta-2 adrenergic receptor in oral squamous cell carcinoma.
Bravo-Calderon DM, Oliveira DT, Marana AN, Nonogaki S, Carvalho AL, Kowalski LP.
Cancer Biomark. 2011-2012;10(1):51-9. doi: 10.3233/CBM-2012-0228.
PMID 22297552
Switching of the coupling of the beta2-adrenergic receptor to different G proteins by protein kinase A.
Daaka Y, Luttrell LM, Lefkowitz RJ.
Nature. 1997 Nov 6;390(6655):88-91.
PMID 9363896
Molecular mechanisms of beta(2)-adrenergic receptor function, response, and regulation.
Johnson M.
J Allergy Clin Immunol. 2006 Jan;117(1):18-24; quiz 25. (REVIEW)
PMID 16387578
Norepinephrine and beta 2-adrenergic receptor stimulation regulate CD4+ T and B lymphocyte function in vitro and in vivo.
Kohm AP, Sanders VM.
Pharmacol Rev. 2001 Dec;53(4):487-525. (REVIEW)
PMID 11734616
Epinephrine stimulates esophageal squamous-cell carcinoma cell proliferation via beta-adrenoceptor-dependent transactivation of extracellular signal-regulated kinase/cyclooxygenase-2 pathway.
Liu X, Wu WK, Yu L, Sung JJ, Srivastava G, Zhang ST, Cho CH.
J Cell Biochem. 2008b Sep 1;105(1):53-60. doi: 10.1002/jcb.21802.
PMID 18452159
beta2 Adrenoceptor signaling-induced muscle hypertrophy from blood flow restriction: is there evidence?
Loenneke JP, Wilson JM, Thiebaud RS, Abe T, Lowery RP, Bemben MG.
Horm Metab Res. 2012 Jun;44(7):489-93. doi: 10.1055/s-0032-1314787. Epub 2012 May 25. (REVIEW)
PMID 22638833
Stress-related mediators stimulate vascular endothelial growth factor secretion by two ovarian cancer cell lines.
Lutgendorf SK, Cole S, Costanzo E, Bradley S, Coffin J, Jabbari S, Rainwater K, Ritchie JM, Yang M, Sood AK.
Clin Cancer Res. 2003 Oct 1;9(12):4514-21.
PMID 14555525
Molecular mechanisms of beta2-adrenergic receptor function and regulation.
McGraw DW, Liggett SB.
Proc Am Thorac Soc. 2005;2(4):292-6; discussion 311-2. (REVIEW)
PMID 16267351
The structure and function of G-protein-coupled receptors.
Rosenbaum DM, Rasmussen SG, Kobilka BK.
Nature. 2009 May 21;459(7245):356-63. doi: 10.1038/nature08144. (REVIEW)
PMID 19458711
Epinephrine protects cancer cells from apoptosis via activation of cAMP-dependent protein kinase and BAD phosphorylation.
Sastry KS, Karpova Y, Prokopovich S, Smith AJ, Essau B, Gersappe A, Carson JP, Weber MJ, Register TC, Chen YQ, Penn RB, Kulik G.
J Biol Chem. 2007 May 11;282(19):14094-100. Epub 2007 Mar 12.
PMID 17353197
Expression of beta2-adrenergic receptor in oral squamous cell carcinoma.
Shang ZJ, Liu K, Liang de F.
J Oral Pathol Med. 2009 Apr;38(4):371-6. doi: 10.1111/j.1600-0714.2008.00691.x. Epub 2008 Dec 30.
PMID 19141064
Stress-mediated increases in systemic and local epinephrine impair skin wound healing: potential new indication for beta blockers.
Sivamani RK, Pullar CE, Manabat-Hidalgo CG, Rocke DM, Carlsen RC, Greenhalgh DG, Isseroff RR.
PLoS Med. 2009 Jan 13;6(1):e12. doi: 10.1371/journal.pmed.1000012.
PMID 19143471
Stress hormone-mediated invasion of ovarian cancer cells.
Sood AK, Bhatty R, Kamat AA, Landen CN, Han L, Thaker PH, Li Y, Gershenson DM, Lutgendorf S, Cole SW.
Clin Cancer Res. 2006 Jan 15;12(2):369-75.
PMID 16428474
Adrenergic signaling in human oral keratinocytes and wound repair.
Steenhuis P, Huntley RE, Gurenko Z, Yin L, Dale BA, Fazel N, Isseroff RR.
J Dent Res. 2011 Feb;90(2):186-92. doi: 10.1177/0022034510388034. Epub 2010 Dec 2.
PMID 21127260
Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma.
Thaker PH, Han LY, Kamat AA, Arevalo JM, Takahashi R, Lu C, Jennings NB, Armaiz-Pena G, Bankson JA, Ravoori M, Merritt WM, Lin YG, Mangala LS, Kim TJ, Coleman RL, Landen CN, Li Y, Felix E, Sanguino AM, Newman RA, Lloyd M, Gershenson DM, Kundra V, Lopez-Berestein G, Lutgendorf SK, Cole SW, Sood AK.
Nat Med. 2006 Aug;12(8):939-44. Epub 2006 Jul 23.
PMID 16862152
Norepinephrine upregulates VEGF, IL-8, and IL-6 expression in human melanoma tumor cell lines: implications for stress-related enhancement of tumor progression.
Yang EV, Kim SJ, Donovan EL, Chen M, Gross AC, Webster Marketon JI, Barsky SH, Glaser R.
Brain Behav Immun. 2009 Feb;23(2):267-75. doi: 10.1016/j.bbi.2008.10.005. Epub 2008 Oct 21.
PMID 18996182
Norepinephrine up-regulates the expression of vascular endothelial growth factor, matrix metalloproteinase (MMP)-2, and MMP-9 in nasopharyngeal carcinoma tumor cells.
Yang EV, Sood AK, Chen M, Li Y, Eubank TD, Marsh CB, Jewell S, Flavahan NA, Morrison C, Yeh PE, Lemeshow S, Glaser R.
Cancer Res. 2006 Nov 1;66(21):10357-64.
PMID 17079456
Integrative genomics analysis reveals silencing of beta-adrenergic signaling by polycomb in prostate cancer.
Yu J, Cao Q, Mehra R, Laxman B, Yu J, Tomlins SA, Creighton CJ, Dhanasekaran SM, Shen R, Chen G, Morris DS, Marquez VE, Shah RB, Ghosh D, Varambally S, Chinnaiyan AM.
Cancer Cell. 2007 Nov;12(5):419-31.
PMID 17996646
beta-arrestin2 mediates beta-2 adrenergic receptor signaling inducing prostate cancer cell progression.
Zhang P, He X, Tan J, Zhou X, Zou L.
Oncol Rep. 2011 Dec;26(6):1471-7. doi: 10.3892/or.2011.1417. Epub 2011 Aug 10.
PMID 21833475


This paper should be referenced as such :
DT Oliveira, DM Bravo-Calderón
ADRB2 (adrenoceptor beta 2, surface)
Atlas Genet Cytogenet Oncol Haematol. 2014;18(9):659-662.
Free journal version : [ pdf ]   [ DOI ]

External links

HGNC (Hugo)ADRB2   286
Entrez_Gene (NCBI)ADRB2    adrenoceptor beta 2
GeneCards (Weizmann)ADRB2
Ensembl hg19 (Hinxton)ENSG00000169252 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000169252 [Gene_View]  ENSG00000169252 [Sequence]  chr5:148826611-148828623 [Contig_View]  ADRB2 [Vega]
ICGC DataPortalENSG00000169252
TCGA cBioPortalADRB2
Genatlas (Paris)ADRB2
SOURCE (Princeton)ADRB2
Genetics Home Reference (NIH)ADRB2
Genomic and cartography
GoldenPath hg38 (UCSC)ADRB2  -     chr5:148826611-148828623 +  5q32   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)ADRB2  -     5q32   [Description]    (hg19-Feb_2009)
GoldenPathADRB2 - 5q32 [CytoView hg19]  ADRB2 - 5q32 [CytoView hg38]
Genome Data Viewer NCBIADRB2 [Mapview hg19]  
OMIM109690   600807   601665   
Gene and transcription
Genbank (Entrez)AA886615 AK223025 AK313151 AY136741 BC012481
RefSeq transcript (Entrez)NM_000024
Consensus coding sequences : CCDS (NCBI)ADRB2
Gene ExpressionADRB2 [ NCBI-GEO ]   ADRB2 [ EBI - ARRAY_EXPRESS ]   ADRB2 [ SEEK ]   ADRB2 [ MEM ]
Gene Expression Viewer (FireBrowse)ADRB2 [ Firebrowse - Broad ]
GenevisibleExpression of ADRB2 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)154
GTEX Portal (Tissue expression)ADRB2
Human Protein AtlasENSG00000169252-ADRB2 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Conserved Domain (NCBI)ADRB2
Human Protein Atlas [tissue]ENSG00000169252-ADRB2 [tissue]
Protein Interaction databases
Ontologies - Pathways
PubMed499 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Fri Oct 8 21:11:56 CEST 2021

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